Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels

Which FT3, FT4 and TSH levels have the highest and lowest prevalence rates for 10 common health disorders?

  1. Hypertension
  2. Hyperlipidemia (high cholesterol)
  3. Depression
  4. Diabetes
  5. Coronary artery disease
  6. Heart failure
  7. Atrial fibrillation
  8. Peripheral vascular disease
  9. Renal failure (kidney failure)
  10. Dementia

Is high-normal TSH and low FT3 associated with one condition, while high-normal FT4 and low or high TSH strongly associated with another condition?

Or do they all have a generally similar pattern of strong disease associations with certain thyroid hormone levels?

Anderson et al, 2020 collected data from the medical charts of 174,914 adults from 1999 to 2018 and associated their diagnoses at the time of their FT4, TSH, and FT3 thyroid laboratory tests.

The researchers provided this rich treasure trove of data in appendix tables. However, their article focused only on atrial fibrillation risk and singled out the FT4 hormone because of their chosen data analysis methods.

Here I bring Anderson and team’s appendix data set into focus through visual and verbal analyses their article had no time or space to provide.

In the 10 data tables, the visual patterns will jump out through heat maps that color-code higher and lower prevalence rates in a grid of 18 hormone categories (6 levels per hormone x 3 hormones).

Each disease’s table comes with a scientific discussion of its puzzles and patterns that you can click to expand. Read quotations from other scientists that noticed similar patterns and commented on them.

At the end, tables summarize rankings of prevalence rates: One gives the average rank of prevalence rates across all 10 disorders and the other focuses on 4 cardiovascular disorders.

What can we learn from this comparison?

  • Normal TSH levels rarely associated with the lowest rates of these disorders, which is unexpected given prevailing beliefs about the safety of normal TSH.
  • Abnormally high or low TSH categories rarely had the highest prevalence rates for these disorders, which is also unexpected for the same reason.
  • Instead, FT4 and FT3 levels usually had the highest and lowest prevalence rates.
  • TSH and FT4 levels in high-normal range often had higher prevalence rates than extremely high or low levels, which is puzzling.
  • FT3 and FT4 prevalence rates often trended in the opposite direction from each other. This shows that the human body responds differently to these two forms of thyroid hormone in circulation.
  • Hormone categories with lower average FT3:FT4 ratios often correlated with higher disease prevalence rates. Therefore, the hormone relationships matter, not just their levels.

Why has it been so difficult for scientists and doctors to see these patterns emerge in disease prevalence rates? What are the implications of long term medical blindness to the power of FT3 levels and FT3:FT4 ratios in human health? What do the data mean for treated thyroid patients? I’ll give some suggestions for action.

Copyright fair dealing note

Quotation, paraphrase, and reproduction, annotation, and adaptation of graphs and tables from copyrighted scientific publications is acceptable within the terms of Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info

How did Anderson and team obtain their data?

In a health care region in the northwestern United States, medical records between 1999 and 2018 were searched.

  • Adults over 18 years old, 174,914 were chosen if they had a FT4 lab test and were not treated with thyroid medications. The date of this FT4 test was considered their “study entry” date.
  • Among these people, 147,834 had a TSH test within 60 days of their study entry.
  • Among these people, 26,524 also had a FT3 test within 60 days.

On average, people had one, two, or three of these these tests within a period of only 2 days.

The population’s official diagnostic codes for atrial fibrillation and 9 other chronic diseases at the time of this set of tests were recorded. Therefore, the research team tabulated disease association rates with each subcategory of hormone levels.

Anderson’s article, titled “Free thyroxine within the normal reference range predicts
risk of atrial fibrillation,”
focused on one disorder — atrial fibrillation (AF).

See our article that focuses only on the atrial fibrillation (AF) data set.

Why are these unadjusted prevalence rates worthy of analysis?

For advanced scientific readers: Click to expand

While the prevalence data set is rich and interesting, Anderson and team’s analysis methods to adjust for confounding variables and to calculate hazard ratios (risk) relied on problematic assumptions and procedures critiqued in other medical research literature.

In short, Anderson and team only looked for linear trends within reference that were unique for atrial fibrillation.

They then found that high-normal FT4 fit the narrow pattern they were looking for within the narrow range they were interested in.

Their method of analysis ignored the stronger, non-linear U-shaped patterns of prevalence rates in FT3 and TSH, as if only “linear trends” matter for human health. In some cases, like thyroid hormones, the very same health disorder may occur at both higher and lower concentrations of hormone. It is well known that various types of cardiovascular disease occur in both extremes of hyperthyroidism and hypothyroidism (Zhang et al, 2019). This parallel risk at both ends of a spectrum creates a “U-shaped” pattern of risk on a line graph.

Anderson’s methods of adjustment also incorporated an “overadjustment bias” by unnecessarily adjusting for the prevalence rates of too many other cardiovascular conditions (presumably the many conditions in their appendix tables) that, like AF, also had strong disease associations with low FT3 and high-normal TSH.

Anderson and team also deemphasized FT4 and FT3 hormone levels beyond the reference range (despite a large percentage of their population having values beyond their laboratory’s ranges). This choice made them ignore the higher rates for AF in the High FT4 and Low FT3 categories. The human body does not monitor laboratory reference ranges and treat them as barriers. One or another hormone may go above or below the statistical normal range during illness. Research must see what nature really does and then use the natural patterns to create groups of data for analysis.

Therefore, looking at their raw, unadjusted, and unanalyzed data set is better than looking through the lens of their biased analytical procedures.

There’s so much to learn from the diverse data in their appendix. It’s a treasure-hoard of rich data that show patterns that map onto emerging research on TSH, FT4, and FT3 in various diseases.

For more information about their methods, consult their original article available in full online. See my basic critique in our blog post introducing their main unadjusted data set, “Anderson, 2020: Thyroid hormones and atrial fibrillation“.

How to read Anderson’s data

In the tables below, each hormone has six levels from low to high:

  1. Low,
  2. Normal Q1,
  3. Normal Q2,
  4. Normal Q3,
  5. Normal Q4,
  6. High

The four divisions within in reference range are “quartiles.”

The reference ranges were:

  • FT4: 0.75 to 1.50 ng/dL
  • TSH: 0.54 to 6.80 mcIU/L (Units equal to mU/L; 0.4 to 4.0 is more common.)
  • FT3: 2.40 to 4.20 pg/mL (100x smaller than the usual unit for FT3, pg/dL)

Where do the 4 Quartiles fit within reference range?

Anderson and team put all the people with “Normal FT4” and divided them into four equal sized groups, and did the same for the other two data sets. Dividing data into (3) tertiles, (4) quartiles or (5) quintiles is standard practice.

This resulted in each group covering a different portion of each reference range.

  • Notice the pink gridlines representing the reference ranges for the hormones.
  • Notice the size of Q4 on the right hand side of the diagram. Anderson’s “Normal Q4” quartile encompassed most or all of the upper half of reference range for each hormone. Q1, Q2, and Q3 cover narrower regions in the lower half of the reference ranges.

The TSH upper limit is controversial. In the region of the US where the study was conducted, the TSH limit was raised significantly near the very end of the study period. Their “Normal Q4” includes TSH values up to 6.80 mIU/L. (See “Details on methods” below). This means that some people with subclinical hypothyroidism were misclassified in Normal Q4.

Caution: These data are only from people on NO thyroid therapy.

The following prevalence rates are associations found in UNtreated individuals.

Therefore, these associations cannot translate to simple prescriptions or risk estimates for treated thyroid patients’ hormone levels.

Thyroid disease and its treatments distort TSH-FT4-FT3 hormone relationships even when they may “normalize” TSH and FT4.

The prevalence rates you see below will be different in various populations of treated thyroid patients on different thyroid hormone treatments — levothyroxine (LT4), liothyronine (LT3), porcine desiccated thyroid, and combinations.

There is no simple way to minimize disease risk in a hormone-treated person whose FT3:FT4 ratio and/or TSH-FT3 relationship is abnormal during thyroid therapy. In some patients with central hypothyroidism, the HPT axis is untrustworthy, and TSH is lower than it should be per unit of FT4 and FT3 because of dysfunctional TSH secretion.

Application of research must be approached with great caution to people who were not the main research population in this study. There is a little bit of data on treated patients’ atrial fibrillation risk in Anderson’s study, but their thyroid disease etiologies, antibodies, thyroid gland health, and dose changes were not followed.

The 10 chronic disorders

1. Hypertension

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]

Hypertension prevalence rates: Discussion
49.2%Average rate across all hormone levels
% below averageCategory% above averageCategory
-0.5%High FT45.5%FT4 Normal Q4
2.4%TSH Normal Q2 9.9%High TSH
-13.9%High FT33.1%Low FT4
Hypertension data analysis

In this population NOT treated with thyroid hormones,

  • High TSH (>6.80 mU/L) had the highest prevalence rate of hypertension, 59.1%.
    • These people would be diagnosed either with subclinical hypothyroidism (if TSH >10 but FT4 “normal”) or overt hypothyroidism (if low FT4, especially if TSH >10).
  • High FT3 with overt hyperthyroidism and a high FT3:FT4 ratio had the lowest prevalence rate for hypertension, 35.3%.

Puzzles and patterns

1. Low FT3 is not the highest prevalence rate. This is unusual considering the patterns that show up in this list below. It suggests that in this disorder, lack of T3 signaling is worsened by a high TSH. Therefore, scientists should consider the independent role of TSH receptor signaling on the cardiovascular system.

2. Low TSH versus High FT3. The cohorts in these two categories share a low average TSH. Why is the prevalence rate 18.5% higher for hypertension in the Low TSH category? Notice that in the Low TSH category:

  • the FT3:FT4 ratio is not as high,
  • the FT4 is significantly higher than all quartiles of FT3 in the normal range, and that FT4 in Normal Q4 has an almost equal rate.
  • Between these two hormone level categories, the shared feature of the average low TSH is not as significant as the two thyroid hormones.

These findings may appear paradoxical to some people because hypertension (high blood pressure) is usually associated with a low heart rate, and lower heart rate is associated with hypothyroidism. Yet hypothyroidism had the highest prevalence rate for hypertension!

However, “thyroid & cardiology” experts know about this association.

Stabouli et al (2010) write:

Hypothyroidism has been recognized as a cause of secondary hypertension.

Previous studies on the prevalence of hypertension in subjects with hypothyroidism have demonstrated elevated blood pressure values.”

In their section on “Mechanisms of Hypothyroidism-related Hypertension,” Stabouli and team explain:

“3,5,3′-triiodothyronine [T3 hormone] represents the metabolically active thyroid agent that possibly has a vasodilatory effect on the vascular muscle cells.”

Dilating blood vessels relaxes them. That’s what T3 does.

On the other end of the spectrum, the lower FT3 end,

Hypothyroidism and T3 deficiency are associated with peripheral vasoconstriction. 

DII [D2, deiodinase type 2] was identified in cultured human coronary and aortic arterial smooth muscle cells.

DII is believed to be responsible for the local conversion of T4 to T3 in these vessels.”

In addition, Stabouli et al explain that low T3 levels can lead to renal (kidney) dysfunction (see “Renal Failure” rates below). Kidney disorders can affect blood pressure and lead to other cardiovascular problems.

Low T3 hypothyroidism can cause dysfunction with the renin–angiotensin–aldosterone system (RAAS), which “is important for medium- and long-term BP regulation.” (Stabouli et al, 2010)

A few more patterns…

3. U-shaped (or J-shaped) pattern in TSH levels. The rate is lowest in Q2. Rates of hypertension are significantly worse in High TSH than low.

4. Rising linear trend in FT4 levels until High FT4. The higher the FT4, the higher the prevalence rate for hypertension. However, the higher FT3:FT4 ratio in the High FT4 category breaks the trend.

5. Falling linear trend in FT3 levels. The higher the FT3, the lower the prevalence rate for hypertension.

2. Hyperlipidemia

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Hyperlipidemia prevalence rates: Discussion
48.2%Average prevalence rate across all hormone levels
% below averageCategory  % above averageCategory
-6.3%High FT43.4%FT4 in Normal Q2
-5.3%High TSH6.1%TSH in Normal Q2
-9.6%High FT30.2%FT3 in Normal Q1
Hyperlipidemia data analysis

In this population NOT treated with thyroid hormones,

  • TSH in Normal Q2 (1.31‐2.04 mU/L) had the highest prevalence rate of high cholesterol, 54.3%.
    • There was not much difference among three TSH levels in normal range. They all had high prevalence rates.
    • Normal TSH does not seem to be protective.
  • High FT3 with overt hyperthyroidism and a high FT3:FT4 ratio had the lowest prevalence rate for hyperlipidemia, 38.6%.

Puzzles and patterns

The high prevalence in the middle of the TSH reference range, which is unlike any other association pattern found among the 10 disorders listed here.

It also seems contradictory to find high prevalence rates here when “Subclinical hypothyroidism is known to be associated with increased serum cholesterol.” (Moreno-Navarrete et al, 2017)

However, in Anderson’s study, the TSH in Normal Q4 went up to 6.80 mIU/L, which offers a clue as to why this category had a high prevalence rate. Many patients with subclinical hypothyroidism were designated subclinical hypo prior to the significant rise in the upper TSH range boundary in 2017.

FT3 signaling offers a more significant clue to this puzzle.

  • Overall, with one exception (the Highest TSH category, which had a low FT3), high cholesterol seemed to be less prevalent when FT3 was higher.
  • Even the form of overt hypothyroidism with the highest FT3 (in the Low FT4 category, with a FT3 well in reference range), had a relatively low rate of hyperlipidemia.
  • None of the normal-range TSH categories had a FT3 higher than 23% of reference range, limiting the mere presence of “Normal TSH” from having an effect on lowering cholesterol.

T3 signaling reduces cholesterol

When Martin et al, 2017 analyzed Total T3 as a continuous variable, they found a linear inverse relationship between T3 and cholesterol throughout and beyond the T3 reference range:

“For each doubling in T3, non-HDL-C [cholesterol] was lower by 18.0 mg/dL (95% CI: 15.2 to 20.8; P < 0.001) and LDL-C [cholesterol] by 18.7 mg/dL (95% CI: 16.2 to 21.2; P < 0.001).”

As explained by Mullur et al, 2014, T3 hormone powerfully reduces the rate of cholesterol synthesis through multiple signaling pathways.

TSH signaling raises cholesterol

In contrast with the relationship of high T3 [and FT3] to low cholesterol, TSH signaling raises cholesterol:

“A positive association between serum thyroid-stimulating hormone (TSH) levels and atherogenic lipid profile, including total cholesterol, LDL cholesterol, and fasting triglyceride levels, is well known”

Moreno-Navarrete et al, 2017

In short, the TSH receptor, when activated, can powerfully drive up cholesterol biosynthesis in the liver.

Q: Why then did the high TSH category, the form of overt hypothyroidism with low FT3 and the highest TSH, have low prevalence for hyperlipidemia?

I would like to propose something not considered by cardiovascular researchers. TSH receptor signaling can be blocked in autoimmune hypothyroidism.

TSH receptor-blocking antibodies may limit cholesterol escalation despite a lower FT3 and higher TSH.

An unknown portion of subjects in the extreme high TSH category may have had TSH-receptor blocking antibodies (TBAb), which some studies have found in up to 46% of Atrophic Thyroiditis patients (a form of autoimmune hypothyroidism previously designated “primary myxedema” and “agoitrous” or “nongoitrous” hypothyroidism), and up to 36% of Hashimoto’s Thyroiditis patients (Diana et al, 2019).

These TBAb have the opposite effect of Graves’ disease antibodies at the TSH receptor. When these antibodies bind to the TSH receptor, instead of enhancing the TSH receptor signal, they block it to a level below even the constitutive signaling of an empty TSH receptor, as shown by McLachlan and Rapoport in 2013:

“The TSHR, similar to many receptors, has a degree of ligand-independent or constitutive activity […].

TSHR ligands (TSH or TSAb) further increase receptor activity […].

An inverse agonist [such as TBAb] suppresses constitutive activity [of the TSH receptor].”

It has long been known that “thyroid-blocking antibodies (TBAbs) have been shown to exhibit inverse agonist properties at TSHR” (Neumann et al, 2010). They block the TSH-receptor signal.

Here’s the paradox. Patients with TBAb activity can have an extremely high TSH level, 80 – 500 mIU/L. However, even a high amount of TSH hormone circulating in blood is unable to activate its blocked receptors in the thyroid gland and throughout the body. This blockage of the TSH-receptor signal and the resulting cAMP signal in cells lowers the FT3:FT4 ratio by downregulating the two main deiodinases that convert T4 to T3. Low levels of T3 in the pituitary gland also drive up TSH secretion very high, but it’s ineffectual TSH.

As the TBAb antibody not only blocks but inverts the TSHR signal, circulating TSH cannot enhance cholesterol synthesis in the liver.

The blocking antibody, which is rarely tested in clinical practice, may explain an apparent paradox: Some people with subclinical hypothyroidism (likely without the TBAb antibody with a mildly elevated TSH) can have a higher cholesterol than patients with overt hypothyroidism and excessively high TSH.

One really has to ask not just “how much TSH is in circulation” but “how much TSH-receptor signaling is possible, given the person’s antibody levels?

3. Depression

[T[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Depression prevalence rates: Discussion
25.3%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
-8.1%High FT42.5%Low FT4
-5.7%High TSH2.8%TSH in Normal Q2
-3.5%High FT35.3%Low FT3
Depression data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for depression, 30.6%.
    • Normal TSH does not seem to be protective.
    • Normal FT3 is not protective unless there is a high FT3:FT4 ratio.
  • High FT4 had the lowest prevalence rate for depression, 17.2%.

Both High FT3 and High FT4 seem to be helpful in depression.

Strangely, only one type of hypothyroidism has a low rate of depression: the one with the highest TSH.

Puzzles and patterns

The concentration of blue in the upper-right corner of the heat map and concentration of pink in the opposite corner is a pattern not seen in the other 9 disorders discussed here.

T3 treatment in psychiatry: The extremely high association of depression with Low FT3 makes one consider this may be one reason why T3 hormone therapy has often been pursued as a way of treating depression that is resistant to common depression medications. In a recent review, it was reported that

“T3 may increase serotonergic neurotransmission and has been studied as an add-on agent in patients with unipolar depression with and without thyroid dysfunction to accelerate, enhance, and augment the effects of tricyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs].”

Morin, 2015

Only one type of hyperthyroidism was more associated with depression: Subclinical hyperthyroidism with high-normal thyroid hormones.

The other two types of hyperthyroidism were different because thyroid hormones were abnormally high.

The lower rates of depression with higher FT4 contradicts many mainstream and alternative medicine teachings about avoiding high FT4.

If high FT4 is harmful for cardiovascular health but beneficial for depression, a healthy compromise may be found by increasing the FT3 instead of the FT4, and most certainly, by avoiding a low FT3.

Why does the highest TSH category associate so poorly with depression, compared with the Low FT4 category? That is the most puzzling pattern of all. Their prevalence rates are almost opposite.

  • Here’s one clue — the FT4 is significantly higher in the High TSH category, and in general, FT4 seems to give a linear pattern of association.

The way the brain metabolizes thyroid hormones

According to Mohácsik et al, 2011,

“a significant amount of brain T3 is derived from the local activation of prohormone T4 to T3 (80% in the cortex), suggesting that most T3 acting in the brain is generated in situ from T4 deiodination.

Normally, the brain depends more on T4 converting locally to T3, and it depends relatively less on Free T3 being transported into the brain. This could explain why FT4 is so important to the brain.

The brain predominantly expresses two deiodinases for conversion: D2 and D3. (This is different from other organs like the thyroid, the organ that expresses the most D1 and D2, with hardly any D3.)

The brain plays a sort of internal game of football between glial cells and neurons as explained by Mohácsik and team:.

“D2 is expressed in glial cells” […]

So the glial cells convert T4 to T3.

“D3 expression in the brain is restricted to neurons”

So, the neurons get rid of any excess T4 and T3 by converting T4 to RT3 and T3 to T2.

In this way, they cooperate:

glial D2 provides T3 for neighboring neurons that express TR [thyroid receptors] but lack T3 generating capacity”

Glial cells donate T3 to the neurons, and the FT3 that is sent off to neurons mixes with other FT3 in brain circulation.

The neurons have the thyroid receptors in them, but they can’t make their own local T3, so they have to depend on T3 donations 1) by T4-T3 conversion in glial cells, and 2) from FT3 crossing the blood-brain-barrier via MCT8 transporter.

The neurons also have to protect their receptors from being flooded by excess T3, so they are equipped with D3 to clear out any excess T4 and T3 that enter their cells.

Free T3 is still important!

Even though FT4 is the major source of hormone, the brain still needs Free T3 to top up locally generated T4-T3 conversion supply.

Being equipped with the ability to get rid of excess hormone (D3 has no known limit to its upregulation), the brain does far better with a slight excess of T3 than with a deficiency of FT3 crossing the BBB on transporters like MCT8.

If there is not enough locally-generated T3, and not enough peripheral FT3 entering brain to make up for the shortfall, the brain will become hypothyroid. This explains the high rate of prevalence for depression in the Low FT3 category.

FT3 becomes even more important if a person has a genetic polymorphism in their DIO2 gene. Jo et al, 2019 say

“Thr92Ala-DIO2 carriers do not produce sufficient amounts of T3 via D2.”

However, this usually becomes a bigger problem when the thyroid gland loses function and people are on T4 thyroid therapy:

“carriers of the Thr92Ala-DIO2 polymorphism are reportedly asymptomatic when surveyed through quality of life or thyroid-specific questionnaires.

“A phenotype has only been reported in connection with diagnosis and treatment for hypothyroidism”

It’s at this point that the brain feels the lower-than-average Free T3 levels commonly found in T4-monotherapy treated hypothyroidism ADDED to the even lower FT3 levels caused by a weaker D2 enzyme in glial cells!

Jo and team point out that

“the approximately 10% lower serum T3 levels observed in adequately LT4-treated hypothyroid patients could be the key element that tips the balance toward behavioral and cognitive dysfunction.”

The brain is used to having that FT3 floating around to top up the rate of local T4-T3 conversion, but now even the rate of local conversion is lower. It’s a double handicap.

Therefore, treatment with some T3 hormone makes sense in carriers, according to Jo et al, 2019:

” it would seem logical to explore further the sensible use of LT3 when treating hypothyroid carriers of the Thr92Ala-DIO2 polymorphism.” 

4. Diabetes

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Diabetes prevalence rates: Discussion
18.9%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
0.0%Low FT44.1%FT4 in Normal Q4
-0.4%High TSH2.8%TSH in Normal Q3 and Q4
-7.5%High FT34.4%Low FT3
Diabetes data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for diabetes, 23.3%.
    • Normal TSH does not seem to be protective.
  • High FT3 had the lowest prevalence rate for diabetes, 11.4%.
    • Normal FT3 is increasingly protective as it rises.

Puzzles and patterns

TSH is almost irrelevant for this disorder, as one can see only light shades of pink and blue in the line of TSH levels. FT3 and FT4 carry the emphasis for low and high prevalence rates.

  • Among the three types of hyperthyroidism seen in the dat set, only subclinical hyper is more associated with diabetes. The other two types of overt hyper had low diabetes rates.
  • Paradoxically, overt hypothyroidism, is not associated with high rates of diabetes. Only “tissue hypothyroidism” is associated because it is characterized by low T3.

The contrast is stark between FT4 in Normal Q4 and low FT3, with an almost similar rate of prevalence (23% vs 23.3%).

Instead, T3 and TSH have complex relationships to diabetes, as explained by Zhang et al, 2018:

  • T3 signaling enhances gluconeogenesis in liver. Metformin (diabetes medication) hinders gluconeogenesis in liver.
  • “TSH is also associated with hyperinsulinemia and insulin resistance.”

However, T3 signaling can also aid diabetes:

“T3 potentiated insulin signaling, improved insulin sensitivity, and increased insulin synthesis, which may contribute to its anti-diabetic effects. These findings may provide new approaches to the treatment of type 2 diabetes.”

[Lin et al, 2011]

It seems that this disorder shifts FT3:FT4 hormone ratios in ways that can worsen diabetes, creating a vicious cycle of low T3 signaling in tissues:

“T2DM reduces thyroid-stimulating hormone levels and impairs the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissues.

[Kalra et al, 2019]

In addition, an isolated low FT3 is associated with diabetic nephropathy. A recent study found that

“Of the 421 patients, 203 (48.2%) suffered from DN, and no difference was found between males and females. The patients with DN yielded significantly lower FT3 levels than those without DN (P < 0.01). The prevalence of DN showed a significantly decreasing trend across the three tertiles based on FT3 levels (59.6%, 46.4%, and 38.6%, P < 0.01).”

Wu et al, 2015

It is clear that one can’t assume that “high thyroid hormones” are always a bad thing for diabetes — one must specify whether FT3 or FT4 is high, because one is relatively benign while the other is less so, and their ratio matters.

Clearly, more study is needed that examines the FT3:FT4 ratio, not just isolated FT3 levels and FT4 levels and diabetes.

5. Coronary artery disease (CAD)

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
CAD prevalence rates: Discussion
16.4%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
-0.5%High FT42.2%FT4 in Normal Q4
0.4%TSH in Normal Q25.5%TSH in Normal Q4
-7.0%High FT34.1%Low FT3
Coronary artery disease – data analysis

In this population NOT treated with thyroid hormones,

  • TSH in Normal Q4 had the highest prevalence rate for CAD, 21.9%.
    • Normal TSH does not seem to be protective.
  • High FT3 had the lowest prevalence rate for CAD, 9.4%.
    • Normal FT3 is increasingly protective as it rises.

Puzzles and patterns

None of the FT4 levels seemed to matter. They are all faintly pastel when color-coded by Microsoft Excel. High FT4 had a mildly lower rate of prevalence.

TSH only had one major “hot spot” for CAD prevalence, and it was hidden within reference in Normal Q4, not likely to be flagged by a blood test result.

Low vs. higher FT3 seems to act as a clear on/off switch for CAD.

The results and conclusions of a recent study underline the importance of FT3 for CAD even within the context of “euthyroid” TSH and FT4 levels:

Single vessel disease was found in 23%, double vessel disease in 15% and triple vessel disease in 17% of patients. TSH and FT4 levels were also comparable between the groups.

Normal coronary group had significantly higher mean FT3 values than triple vessel disease (p=0.004) and FT3 levels showed an inverse relation with Gensini score (Pearson’s correlation =- 0.30) (p =0.002).

A level of FT3 ≤ 2.7 predicted the severity of CAD with a 70% sensitivity and 60% specificity (area under curve (AUC): 0.755, p=0.001).

In the absence of primary thyroid disease and acute coronary syndrome, the occurrence of CAD is associated with lower serum levels of FT3.

FT3 and not the FT4 and TSH levels may be used as an indicator of increased risk for severe CAD.

The present study clearly shows the existence of a strong association between the reduction of biologically active T3 and severity of coronary artery disease.

However, low T3 state could be at first interpreted as just a biological risk factor of severe coronary artery disease; only the demonstration of beneficial effects on cardiovascular, end points of long term T3 replacement in CAD patients with low T3 state can answer this fundamental issue.

Daswani et al, 2015

Fortunately, scientists, a lot of treated thyroid patients have CAD and are maintained on T4 monotherapy. You can try changing their thyroid therapy by including T3 hormone. Some of them will likely be happy to consent to participate, especially if they currently have low FT3:FT4 ratios. Keep them on this therapy for many years with their consent instead of just doing a short-term trial. Check up on them 3 years and 5 years and 10 years later to see how incorporating T3 has changed their health outcomes.

Even more fortunately, a lot of thyroid patients are already on long-term T3-T4 synthetic combination therapy or desiccated thyroid therapy. Recruit them. Study their prevalence rates for CAD today. You don’t have to wait 3-10 years to find out what T3 therapy did for this treated population’s prevalence rates for CAD. You can compare them with the rates of CAD in age- and sex-matched thyroid patients maintained on T4 monotherapy who have a similar thyroid diagnosis (i.e. total thyroidectomy). Cheaper study.

6. Heart failure

[TH = Thyroid hormones FT3 and FT4][See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Heart failure prevalence rates: Discussion
10.5%Average prevalence rate across all hormone levels
% below averageCategory% above averageCategory
0.1%FT4 in Normal Q23.1%FT4 in Normal Q4
-1.1%TSH in Normal Q25.0%TSH in Normal Q4
-6.5%FT3 in Normal Q46.1%Low FT3
Heart failure data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for heart failure, 16.6%.
    • TSH in Normal Q4 had the second highest HF rate.
  • FT3 in Normal Q4 had the lowest prevalence rate for heart failure, 4.0%.
    • Normal FT3 appears to be protective as it rises from Q1 to Normal Q4.

Puzzles and patterns

In this disorder, the “on-off” switch of Low FT3 vs. high normal FT3 is also clear.

We also now have a U-shaped pattern appear in FT4 and TSH levels, with the high and low levels being more associated with heart failure than the lower half of reference range.

Two types of “overt hyper” — with different FT3:FT4 ratios — had very different prevalence rates for HF: 13.4% for a lower ratio, and 5.6% for a higher ratio.

Of relevance here is Pingitore’s clinical trial of T3 therapy in heart failure patients who do not have a thyroid disorder diagnosis:

“Our main finding was that L-T3 infusion induced a positive cardiac and neuroendocrine resetting characterized by improved SV of the left ventricle and deactivation of the neuroendocrine profile, resulting from the significant reduction in vasoconstrictor/sodium retaining noradrenaline, aldosterone, and in the counterpart NT-proBNP plasma levels. […]

Further evidence in favor of an indirect positive effect of T3 on neuroendocrine resetting is the observation of a decreased HR [heart rate].

Pingitore et al, 2008

Kishi et al, 2015 put their main conclusion into their article’s title:

Free triiodothyronine [FT3], not thyroid stimulating hormone [TSH], should be focused on for risk stratification in acute decompensated heart failure”

7. Atrial fibrillation

[[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Atrial fibrillation (AF) prevalence rates: Discussion
9.7%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-1.0%FT4 in Normal Q24.7%High FT4
-1.3%TSH in Normal Q24.0%TSH in Normal Q4
-5.8%FT3 in Normal Q45.9%Low FT3
Atrial fibrillation data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for AF, 15.6%.
    • Normal TSH does not seem to be protective.
    • FT4 levels also have high prevalence rates in the upper range.
  • Normal Q4 FT3 had the lowest prevalence rate for AF, 3.9%.
    • Normal FT3 is increasingly protective as it rises to Q4
    • This contrasts with the FT4 hormone as it rises to Q4, and also rises in prevalence rate.
    • The rate of AF in FT4 in Q4 is 3x the rate found in FT3 in Q4.

Puzzles and patterns

Notice that for AF, the risk jumps from 3.6% to 7.9% between high-normal and high FT3. Why does the risk almost double? And why is this type of hyperthyroidism less risky than the High FT4 category?

  • Notice that the high FT3 category has a high average FT4 alongside it, and the FT3 is the highest on the chart given the Ratio of average FT3:FT4 being 0.50.

Another set of researchers has noticed that FT3 is the most significant variable in atrial fibrillation.

An item not cited in Anderson’s 2020 article is Wei et al’s 2018 study titled:

“U-shaped association between serum free triiodothyronine [FT3] and recurrence of atrial fibrillation after catheter ablation”

Instead of studying AF prevalence or incidence, they studied AF recurrence in 1115 AF patients who underwent catheter ablation procedure.

Their baseline FT3, FT4 and TSH measures were wisely collected before the catheter ablation procedure, before they could not be influenced by Low T3 syndrome induced by surgery. They then analyzed these baseline values in light of AF recurrence after surgery, and the follow up period averaged 723 days (almost 2 years).

Not everyone had a recurrent episode of AF. Only 47.2% did. And thyroid hormones made a difference. Low FT3 made the biggest difference, followed by high FT3, and high-normal FT4 was next in line.

Only 9.8% of patients had a low FT3 and 1.2% had a high FT3 above laboratory reference range, which was 3.8 to 6.0 pmol/L. After dividing the FT3 data into 5 equal groups, the quintile 1 cutoff was 4.07 and quintile 5 cutoff was 5.10.

In the lowest-risk quintile 3 for FT3, Wei’s population had

  • a FT3 of 4.58 pmol/L (35% of the laboratory reference range) [This proves they were not a healthy cohort, since a strong mid-range tendency is found in a healthy population’s average (Ganslmeier et al, 2014)],
  • a FT4 of 11.61 pmol/L (57% of reference), and
  • a TSH of 1.82 mIU/L (28% of reference).

They concluded this:

“A non-linear, U-shaped association was observed between the FT3 categories and arrhythmia recurrence, and both high and low FT3 levels were associated with AF recurrence after catheter ablation.

Regarding FT4, only a high-normal level was found to be associated with AF recurrence after catheter ablation.

No association was found between the normal range of TSH levels and AF recurrence after the procedure.”

Their findings fit with Anderson’s regarding the FT4 and TSH.

Their findings do not fit with Anderson’s regarding the risk of high FT3 levels, but it’s important to offer caution to people who already have AF about how to prevent its recurrence after treatment.

It would have helped to use the FT3:FT4 ratio (which they did not calculate) to distinguish among those with a high FT3 who were more at risk of AF recurrence due to having a high-normal FT4 at the same time as a FT3 in their 5th quintile.

I will leave Wei with the final words on the dangers of lower-normal FT3 and low FT3:

“An intriguing and novel finding was that the lowest quintile of FT3 also related to arrhythmia recurrence (HR = 1.60, 95%CI, 1.26 to 2.03, P < 0.01).

Compared to patients with FT3 levels in the normal range, a low FT3 state was an independent predictor of arrhythmia recurrence after multivariable adjustment (HR = 1.56, 95% CI, 1.23 to 1.97, P < 0.01).”

Wei et al, 2018

8. Peripheral vascular disease (PVD)

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
PVD prevalence rates: Discussion
9.8%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-0.7%High FT41.0%Low FT4 or FT4 in Normal Q3 
0.2%TSH in Normal Q22.2%TSH in Normal Q4
-4.5%High FT33.9%Low FT3

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for PVD [peripheral vascular disease], 13.7%.
    • Normal TSH in Q4 is the next highest rate at 12%.
    • FT4 levels also have high prevalence rates in the upper range.
  • High FT3 had the lowest prevalence rate for PVD, 3.9%.
    • High FT4 had a slightly lower-than-average prevalence rate of 9.1%.

Puzzles and patterns

Wang et al, 2017 found a strong association between peripheral artery disease and both FT3 and the FT3:FT4 ratio:

“The prevalence of PAD decreased according to FT3 quartiles (5.0%, 2.7%, 2.4%, and 1.5%, respectively; P for trend < 0.0001)

and according to the FT3/FT4 ratio quartiles (4.8%, 3.1%, 2.2%, and 1.3%, respectively; P for trend < 0.0001)

Overall,

higher serum FT3 levels within the normal range and increased FT3/FT4 ratio were significantly associated with a decreased risk of prevalence of PAD.

They say no significance with TSH or FT4, but there is a bit of a U shaped risk in their graphs.

9. Renal failure

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Renal failure prevalence rates: Discussion
6.6%Average rate across all levels and hormones
% below averageCategory% above averageCategory
-1.2%High FT43.2%Low FT4
-0.7%TSH in Normal Q22.7%Low TSH
-4.7%FT3 in Normal Q48.1%Low FT3
Renal failure data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for renal failure, 14.7%.
    • No other hormone level category came near the high prevalence rate for Low FT3.
  • High-normal FT3 in Q4 had the lowest prevalence rate for renal failure, 1.9%.
    • No other hormone level category came near the low prevalence rates for higher levels of FT3

Puzzles and patterns

It appears that for kidney health, the FT3 concentration is an on/off switch.

Long ago, it was discovered that rat Kidney and Liver depended mainly on circulating FT3 to fill their T3 receptors in cells (Silva et al, 1978). These organs depend to a very limited degree on local T4-T3 conversion to meet their T3 receptor occupancy needs. The kidney needs adequate circulating FT3 more than it needs normal FT4.

Iglesias et al, 2017 in a research review titled “Thyroid dysfunction and kidney disease: an update” associate Low T3 with cardiac risk and inflammation in renal failure. They conclude by recommending FT3 testing:

Low T3 has been associated to different inflammation markers, endothelial activation, malnutrition, and cardiac dysfunction in CKD [chronic kidney disease]. […]

The role of T4 and TSH on morbidity and mortality in renal patients is less defined than T3 […]

Variations in both TSH and FT4 within the normal range appear not to have pathological significance. TSH and FT4 did not affect CVD [cardiovascular disease] and mortality in euthyroid PD [peritoneal dialysis] patients [147].

From these results it seems reasonable to perform a regular assessment of TFT [thyroid function tests] measuring mainly T3, and preferably FT3, for helping estimate the clinical outcome and mortality risk in dialysis population.”

10. Dementia

[See “Why is the average FT3:FT4 ratio important?” and “Details on Calculations”]
Dementia prevalence rates: Discussion
1.8%Average prevalence rate across all hormone levels
% below averageCategoryHighest (% difference from average)
-0.1%High FT40.6%Low FT4
-0.1%TSH in Normal Q20.9%TSH in Normal Q4
-1.4%High FT31.0%Low FT3
Dementia data analysis

In this population NOT treated with thyroid hormones,

  • Low FT3 had the highest prevalence rate for dementia, 2.8%.
    • A close second-place is awarded to high-normal TSH in Q4.
  • High FT3 had the lowest prevalence rate for dementia, 0.4%.
    • No level of TSH or FT4 came close to the reduced rates of prevalence found in higher levels of FT3.

Puzzles and patterns

As it does for renal failure, FT3 appears to control the on-off switch for dementia. And in dementia, upper-normal TSH is also to be avoided.

All three types of hypothyroidism had high rates of prevalence.

There appears to be a mild U-shaped risk relationship with TSH having the lowest prevalence rates in the Q2 of normal range. However, the lowest prevalence rates for TSH pale in comparison to the far lower rates in the normal and upper FT3 levels.

Strangely enough, High FT4 had a mildly below average prevalence rate of 1.7%, but high-normal FT4 and subclinical hyperthyroidism had rates of 2.3%.

Too many publications tout the normalcy of a mildly elevated TSH in the elderly and accept the inevitability of a lower FT3 in aging, a stage of life when dementia is more likely to occur.

Many studies on dementia treat it as part of Alzheimer’s disease.

Quinlan and team in 2019 wrote an article announcing in its title that “Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer’s disease.” Their major headings also proclaim what they found:

“Serum TSH and FT4 are not associated with the risk of dementia”

“Serum FT3 is associated with increased risk of conversion to AD [Alzheimer’s Disease]”

The details were as follows:

“Higher serum FT3 was associated with lower risk of conversion to AD [hazard ratio (HR) = 054; 95% confidence interval (CI): 0.32–0.92 per 1 pmol/L increase].

Furthermore, patients in the lowest serum FT3 quartile had a twofold increased risk of AD compared to those in the highest quartile (HR = 2.63; 95% CI: 1.06–6.47).”

However, the study focused on “predictive role of TH [thyroid hormone] in the early disease stages,” so unfortunately “In this study, participants were excluded due to … manifest dementia (n = 206)” Unsurprisingly, with this exclusion of people with dementia, “Serum concentrations of TSH, FT4, and FT3 did not associate with all-cause dementia or VaD [Vascular Dementia].”

Ranking summaries

For each of the 10 disorders, the 18 hormone level categories were ranked from lowest (1) to highest per set, using repeated numbers (5,5,5) when the prevalence rates were identical in two hormone level categories. This was the result:

The boldest colors are in the bottom row. FT3 spans an average prevalence rate ranking from 13.8 to 2.2. The difference between Low FT3 and Normal Q1 FT3 is almost double.

Beyond FT3, the secondary hot spot is TSH in Normal Q4, and the secondary cold spot is High FT4.

Narrowing down the ranking summary to focus only on 4 chronic cardiovascular diseases yields a similar pattern:

FT3 is still the most intense row. Now the step from Low FT3 to Normal Q1 is 3x the distance in the ranking of prevalence rates. High-normal TSH is still the next hot spot.

Now the red color is more evenly distributed. Notice that the 3 types of hypothyroidism (low FT4, high TSH, low FT3) are color coded red.

Why do doctors associate hyper with cardiovascular symptoms and tend to ignore the association with hypo?

Four conclusions

These 10 chronic diseases cost our health care systems a lot of money and can cause great human suffering over a lifetime.

We can’t afford to separate thyroid hormone levels from chronic disease when they give us such major clues about how to manage these diseases more wisely.

Here are some suggested action items:

  1. Distinguish acute from chronic Low T3 syndrome (NTIS)
  2. Treat and prevent low T3 syndrome.
  3. Stop excluding thyroid patients from NTIS study and treatment.
  4. Call for a T3 paradigm shift in thyroid science

1. Distinguish acute from chronic Low T3 syndrome (NTIS)

The data say nothing about the duration of low T3 syndrome, but 15% of the FT3-tested population fit in that category.

The acute (and often benign) phase of NTIS must be distinguished from the pathological state of chronic low T3 that demonstrates a critical failure to recover a vital hormone supply (Moura Neto & Zantut-Wittmann, 2016; Van den Berghe, 2014).

Chronic low Free or Total T3 and chronic low T3:T4 ratios are not just effects of illness, but can also become pathological drivers and maintainers of illness.

Many decades of research in NTIS have shown that a weak TSH response and/or thyroid gland response can perpetuate a low Total or Free T3 level and T3:T4 ratio, leading to increased rates of poor health outcomes and death. (NOTE: In severe illness, the Total T3 is often used instead of Free T3 because some illnesses and blood thinners like heparin can artificially inflate Free hormone test results.)

Look at the T3:FT4 ratios of people with heart failure:

“Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF.”

Kang et al, 2017

The chronic low T3 levels and T3:T4 ratios during chronic disease are prognostic of future problems.

This is the case in many types of chronic illness including renal failure, cardiovascular diseases, not just in acute conditions demanding intensive care (Ataoglu et al, 2018). (See our review of Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.)

2. Treat and prevent chronic low T3 syndrome.

Enough research has catalogued the high rates of death and morbidity in Low T3 Syndrome (also called mistakenly called “euthyroid sick syndrome” just because TSH usually remains normal).

Yet publications continue to repeat the skeptical medical stasis that

no clear consensus has emanated from clinical studies”

of thyroid hormone interventions, so

“many scholars suggest that treatment of the primary disease takes precedence over ESS [euthyroid sick syndrome] intervention.”

Wang et al, 2018

However, quotes like these reveal an arbitrary, false division between the “primary disease” (such as heart failure) and a thyroid hormone metabolism disorder such as ESS, when thyroid hormone signaling clearly modifies primary disease outcomes.

Thyroid scientists with courage have previously advocated for more NTIS treatment trials involving T3 (DeGroot, 2006), but it seems to have fallen on deaf ears. The considerations of treatment are complex, but few have the courage to face them for the sake of saving lives, health care dollars, and human suffering.

If we supply ventilators and oxygen to people who cannot breathe, then it is unethical not to assist the thyroid-healthy human body to recover healthy FT3 levels and FT3:FT4 ratios to prevent the progression of a chronic disease.

Patients with chronic diseases deserve to access FT3 thyroid hormone levels and ratios that are conducive to their recovery.

3. Stop excluding thyroid patients from NTIS study and treatment

This research by Anderson and team unfortunately excluded from their main data set all people dosed with thyroid hormone because of our complexity.

There were 37,288 people excluded from Anderson’s study for this reason. No data tables were provided for them, no explanation of their quartile divisions, and no FT3 or TSH prevalence data was provided. We were only given a verbal summary of the FT4 odds ratios that the researchers felt were most important as they looked for linear trends within the reference range.

This is a significant loss of data. We have insufficient knowledge of a neglected population.

It is very disturbing that thyroid patients are routinely excluded from low T3 syndrome / nonthyroidal illness (NTIS) research, as we’ve discused in previous posts.

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Categories: Cardiovascular, Chronic diseases, Health conditions, Low T3 Syndrome / NTIS, Research Reviews, Thyrotoxicosis, Tissue hypothyroidism

9 replies

  1. Wow, you have done amazing work analyzing the Anderson study! This puts even more weight on the need for a paradigm shift in treatments. It is nice to see these associations in thyroid healthy people, but I hope to see some more studies like this one which would include supplemental T4 & T3 treated subjects each categorized with their DIO mutation profiles or some other measure of the leftover T4 conversion ability.

    I especially liked the way you presented the data for the top 10 chronic diseases. I will bring this to the attention of my endocrinologist when it’s time to negotiate my next T3 raise!

    • Thanks Julien! It was a lot of work, and it helped me learn more. I agree, we need more studies of treated thyroid patients, and a full diversity of patients and treatments — each subtype needs its own analysis.

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